title: Tumor necrosis factor induces tumor promoting and anti-tumoral effects on pancreatic cancer via TNFR1.
abstract: Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+) T cells and CD4(+) forkhead box P3 (FoxP3)(+) regulatory T cells (Treg) but reduced numbers of CD8(+) T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+) T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
authors.affiliation: Department of Internal Medicine II, Würzburg University Clinics, Würzburg, Germany ; Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.forename: Isabell
authors.initials: I
authors.lastname: Lang
authors.forename: Steffen
authors.initials: S
authors.lastname: Salzmann
authors.forename: Christina
authors.initials: C
authors.lastname: Pachel
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kraus
authors.forename: Carina A
authors.initials: CA
authors.lastname: Bäuerlein
authors.forename: Christian
authors.initials: C
authors.lastname: Brede
authors.forename: Ana-Laura Jordán
authors.initials: AL
authors.lastname: Garrote
authors.forename: Katharina
authors.initials: K
authors.lastname: Mattenheimer
authors.forename: Miriam
authors.initials: M
authors.lastname: Ritz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwinn
authors.forename: Carolin
authors.initials: C
authors.lastname: Graf
authors.forename: Viktoria
authors.initials: V
authors.lastname: Schäfer
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D044584:Carcinoma, Ductal / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4